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Discovery of (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidines as novel RORγt inverse agonists.
- Source :
-
Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2020 Sep 01; Vol. 30 (17), pp. 127392. Date of Electronic Publication: 2020 Jul 10. - Publication Year :
- 2020
-
Abstract
- A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC <subscript>50</subscript> of 61 nM in an inverse agonist assay), selective relative to RORα, RORβ, LXRα and LXRβ, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Y <subscript>max</subscript> (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.<br />Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Binding Sites
Crystallography, X-Ray
Drug Inverse Agonism
Humans
Mice
Microsomes, Liver metabolism
Molecular Dynamics Simulation
Nuclear Receptor Subfamily 1, Group F, Member 3 agonists
Pregnane X Receptor agonists
Pregnane X Receptor metabolism
Pyrrolidines chemical synthesis
Pyrrolidines metabolism
Structure-Activity Relationship
Drug Design
Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism
Pyrrolidines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1464-3405
- Volume :
- 30
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Bioorganic & medicinal chemistry letters
- Publication Type :
- Academic Journal
- Accession number :
- 32738966
- Full Text :
- https://doi.org/10.1016/j.bmcl.2020.127392